Bone marrow-derived stem cells incorporate into multiple tissue types in adult mammals, where they give rise to cells of multiple lineages that cross classic embryological trilaminar boundaries [9,11,17,21,31,40,41]. This recent discovery has opened the possibility that bone marrow transplantation could be clinically useful to treat a broad spectrum of pathologies. Recently, marrow-derived progenitor cells have been shown to migrate and incorporate into the brain to give rise to cells of neuroectodermal lineage, (astrocytes and neurons), in addition to microglia [4,7,25]. Importantly, marrow-derived progenitors appear to display preferential homing to regions of CNS gliosis and degeneration [8], consistent with studies in peripheral tissues demonstrating enhanced engraftment of multi-potential marrow-derived stem cells into sites of injury [21,31] [Jackson, 2001 #360]. The focus of the current proposal is to explore the migration and differentiation of marrow-derived stem cells into the brain in a rodent model of Parkinson's disease, the MPTP-treated mouse. Questions to be addressed in this proposal include: Do marrow-derived progenitors display selective homing to the damaged nigra and striatum in response to MPTP-induced degeneration? If so, do they give rise to cells of neuroectodermal lineage? What is their contribution to the gliosis that accompanies nigrostriatal degeneration? To track marrow-derived progenitors within the CNS, we will utilize bone marrow from transgenic mice that express an enhanced green fluorescent protein (GFP) under the beta-actin promoter. The migration and differentiation of marrow-derived progenitors will be studied in chimeric mice whose endogenous hematopoietic systems have been completely reconstituted with GFP-expressing cells prior to MPTP- treatment, and in mice that receive acute intravascular injections of GFP+ expressing cells prior to MPTP-treatment, and in mice that receive acute intravascular injections of GFP+ expressing marrow following the onset of MPTP-induced degeneration. The immediate goal of the proposed studies is to delineate the relationship between marrow-derived progenitors and the brain in a rodent model of Parkinson's disease. If successful, these studies may provide the basis for future work to development new non-invasive gene therapies for Parkinson's disease, using accessible, renewable and autologous bone marrow stem cells.